2003 Fiscal Year Annual Research Report

新規樹立マウスバセドウ病モデルを用いた病態の解析及び治療法の開発

Research Project

Project/Area Number	14571069
Research Institution	Nagasaki University
Principal Investigator	永山雄二長崎大学, 大学院・医歯薬学総合研究科, 教授 (30274632)
Keywords	甲状腺自己免疫 / 甲状腺刺激ホルモン受容体 / アデノウイルス / 自己抗体 / バセドウ病 / サイトカイン
Research Abstract	昨年に引き続き、我々が樹立した新規マウスバセドウ病モデルを用いて疾患の病態解析を進めた。 (1)Th1/Th2免疫バランスとバセドウ病発症:昨年度、Th2サイトカインであるinterleukin-4の共発現でバセドウ病発症が抑制されることを見出したので、本年はさらに、同様にTh2免疫反応を誘導すると言われているalpha-galactosylceramideと寄生虫(マンソン住血吸虫)感染の疾患発症に及ばす影響を検討した。いずれを用いても抗原提示時にTh2偏倚を誘導すると、疾患発症が有意に抑制された。しかし、免疫反応成立後は無効であった。よって、Th2偏倚はバセドウ病の予防効果はあるものの、治療的意義は低いと考えられた。 (2)抗TSH受容体抗体のエピトープ解析:linearエピトープを認識する抗体のエピトープをペプチドを用いて解析し、受容体細胞外領域のN端に位置することを見出した。また、マウスにバセドウ病を誘導するためには、全長受容体遺伝子を用いるより、Aサブユニットをコードする遺伝子を用いる方が効率が上がることを見出した。このことも受容体蛋白N側の抗原性の高さを示唆している。この方法では1/10,000量のアデノウイルス量でも効率よく疾患を誘導できることも見出した。 (3)B細胞欠損マウスを用いて、免疫後のT細胞反応は正常のB細胞の存在が必須であることが明らかとなった。抗原提示細胞としてのB細胞の重要性を示唆していると考えられる。

Research Products

(12 results)

All Other

All Publications (12 results)

[Publications] Nagayama Y.: "A major role of non-major histocompatibility complex genes but not for microorganisms in a novel murine model of Graves' hyperthyroidism"Thyroid. 13(3). 233-238 (2003)
[Publications] Nagayama Y.: "Prevention of autoantibody-mediated Graves'-like hyperthyroidism in mice with IL-4, a Th2 cytokine"Journal of Immunology. 170(7). 3522-3527 (2003)
[Publications] Schwartz-Laurer L.L.: "The cycteine-rich amino-terminus of the thyrotropin receptor is the Immunodominant linear antibody epitope in mice immunized using naked DNA or adenovirus vectors"Endocrinology. 144(5). 1718-1725 (2003)
[Publications] Guo J.: "Insight into antibody responses induced by plasmid or adenoviral vectors encoding thyroid peroxidase, a major thyroid autoantigen"Clinical and Experimental Immunology. 132(3). 408-415 (2003)
[Publications] Chen C.-R.: "The thyrotropin receptor autoantigen in Graves' disease"Journal of Clinical Investigation. 111(2). 1897-1904 (2003)
[Publications] Nagayama Y.: "Enhanced antitumor effect of combined replicative and non-replicative adenovirus expressing interleukin-12"Gene Therapy. 10(16). 1400-1403 (2004)
[Publications] Nagayama Y.: "Novel murine models of thyroid autoimmunity"Current opinion in Endocrinology & Diabetes. 10. 364-370 (2003)
[Publications] Abiru N.: "In vivo expression of B:923 peptide/I-A^<g7> complex may abrogate the inhibition of diabetes induced by RGD-fiber-mutant adenovirus in NOD mice"Annals of New York Academy of Science. 1005. 218-221 (2003)
[Publications] Pichurin P.: "Thyrotropin receptor-specific memory T cell responses require normal B cells in a murine model of Graves' disease"Clinical and Experimental Immunology. 134(3). 396-402 (2003)
[Publications] Saeki A.: "Diverse efficacy of vaccination therapy using the α-fetoprotein gene against hepatocellular carcinoma"International Journal of Oncology. 13(1). 111-116 (2003)
[Publications] Tanaka K.: "Thyroid cancer immuno-therapy with retroviral and adenoviral vectors expressing GMCSF and IL-12 in a rat model"Clinical Endocrinology. 59(6). 734-742 (2003)
[Publications] Chen C.-R.: "Low dose immunization with adenovirus expressing the TSH receptor A-subunit deviates the antibody responses towards that of autoantibodies in human Graves' disease"Endocrinology. 145(1). 228-233 (2004)

2003 Fiscal Year Annual Research Report

新規樹立マウスバセドウ病モデルを用いた病態の解析及び治療法の開発

Principal Investigator

永山 雄二 長崎大学, 大学院・医歯薬学総合研究科, 教授 (30274632)

Research Products

[Publications] Nagayama Y.: "A major role of non-major histocompatibility complex genes but not for microorganisms in a novel murine model of Graves' hyperthyroidism"Thyroid. 13(3). 233-238 (2003)

[Publications] Nagayama Y.: "Prevention of autoantibody-mediated Graves'-like hyperthyroidism in mice with IL-4, a Th2 cytokine"Journal of Immunology. 170(7). 3522-3527 (2003)

[Publications] Schwartz-Laurer L.L.: "The cycteine-rich amino-terminus of the thyrotropin receptor is the Immunodominant linear antibody epitope in mice immunized using naked DNA or adenovirus vectors"Endocrinology. 144(5). 1718-1725 (2003)

[Publications] Guo J.: "Insight into antibody responses induced by plasmid or adenoviral vectors encoding thyroid peroxidase, a major thyroid autoantigen"Clinical and Experimental Immunology. 132(3). 408-415 (2003)

[Publications] Chen C.-R.: "The thyrotropin receptor autoantigen in Graves' disease"Journal of Clinical Investigation. 111(2). 1897-1904 (2003)

[Publications] Nagayama Y.: "Enhanced antitumor effect of combined replicative and non-replicative adenovirus expressing interleukin-12"Gene Therapy. 10(16). 1400-1403 (2004)

[Publications] Nagayama Y.: "Novel murine models of thyroid autoimmunity"Current opinion in Endocrinology & Diabetes. 10. 364-370 (2003)

[Publications] Abiru N.: "In vivo expression of B:923 peptide/I-A^<g7> complex may abrogate the inhibition of diabetes induced by RGD-fiber-mutant adenovirus in NOD mice"Annals of New York Academy of Science. 1005. 218-221 (2003)

[Publications] Pichurin P.: "Thyrotropin receptor-specific memory T cell responses require normal B cells in a murine model of Graves' disease"Clinical and Experimental Immunology. 134(3). 396-402 (2003)

[Publications] Saeki A.: "Diverse efficacy of vaccination therapy using the α-fetoprotein gene against hepatocellular carcinoma"International Journal of Oncology. 13(1). 111-116 (2003)

[Publications] Tanaka K.: "Thyroid cancer immuno-therapy with retroviral and adenoviral vectors expressing GMCSF and IL-12 in a rat model"Clinical Endocrinology. 59(6). 734-742 (2003)

[Publications] Chen C.-R.: "Low dose immunization with adenovirus expressing the TSH receptor A-subunit deviates the antibody responses towards that of autoantibodies in human Graves' disease"Endocrinology. 145(1). 228-233 (2004)

永山雄二長崎大学, 大学院・医歯薬学総合研究科, 教授 (30274632)